A new study investigates the genome-wide patterns of de novo mutations (DNMs) in autism spectrum disorder (ASD) and suggests that the genomes of affected individuals may harbor mutational hotspots (Cell 151, 1431–1442, 2012). Jonathan Sebat and colleagues sequenced the whole genomes of ten pairs of monozygotic twins concordant for ASD and their parents. They found nonrandom positioning of DNMs, with an enrichment of closely spaced DNMs (<100 kb apart). The authors then investigated whether different sequence and chromatin features were associated with mutability, finding that DNase hypersensitivity, GC content, nucleosome occupancy, recombination rate, simple repeats and the trinucleotide sequence around the mutation site significantly influenced mutability. They identified broad genomic regions tens to hundreds of kilobases in length that showed highly elevated mutability (sevenfold higher than the rest of the genome), as well as 'warm spots' showing two- to threefold higher mutability. The authors found that many known autism-associated genes fell within the top 20% of highly mutable exons, and they suggest that hypermutability may be common in disease-related genes. Finally, they note that 34 of their observed DNMs affect protein-coding genes and noncoding RNAs. Together with previously reported DNMs in autism, two novel genes (KIRREL3 and GPR98) are identified that harbor more than one DNM.